ClinVar

Description

The c.1979A>G intronic pathogenic mutation (also known as p.D660G), located in coding exon 12 of the MSH2 gene, results from an A to G substitution at nucleotide position 1979. The aspartic acid at codon 660 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in several probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and/or loss of MSH2 and MSH6 protein expression by immunohistochemistry (Taylor CF et al. Hum. Mutat. 2003 Dec;22:428-33; Sjursen et al. J. Med. Genet. 2010 Sep;47:579-85; Ambry internal data). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), p.D660G was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). In addition, RNA studies using patient samples demonstrated that this alteration led to aberrant splicing resulting in an in-frame partial deletion of coding exon 12 (Sjursen et al. J. Med. Genet. 2010 Sep;47:579-85, personal communication with Dr. Sjursen; Ambry internal data). Furthermore, based on an internal structural analysis, this in-frame deletion of nine amino acids is anticipated to result in a significant decrease in structural stability and is in close proximity to the ATP binding site (Warren et al. Molecular Cell 26, 579–592, May 25, 2007; Gupta S et al. Nat Struct Mol Biol, 2011 Dec;19:72-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.